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Kulesa Lab
Paul Kulesa, Ph.D.
Director of Imaging Center
pmk@stowers-institute.org
Cell Migration: Projects at the Interface of Development and Cancer

Lab Focus: Our laboratory investigates the mechanisms of neural crest migration in the vertebrate embryo and the role of the embryonic microenvironment to reprogram and inhibit adult metastatic cancer.

Lab Techniques: We use molecular biology, tissue transplantation/avian embryo microsurgery, 4D confocal and 2-photon time-lapse imaging, photoactivation of GFP cell labeling, multispectral imaging, and mathematical modeling.

Background and Signficance: The neural crest are an embryonic, highly migratory stem cell-like population that contributes to organ development and the peripheral nervous system. The neural crest also have an ancestral relationship to aggressive cancer cell types making this an excellent model system to study the convergence of embryonic and tumorigenic signaling pathways. Our goal is to identify and examine in vivo the key cellular and molecular mechanisms that regulate neural crest cell migration to gain insight into human birth defects and possible therapeutics to prevent cancer metastasis.

     We consider three major questions:

  • How do neural crest cells interpret signals from the embryonic microenvironment and other cells to migrate to precise peripheral targets in a programmed manner?
  • How do signals within the embryonic microenvironment influence the program and metastatic ability of adult tumor cell types?
  • Can we design innovative cell labeling and imaging strategies to eavesdrop on cell movements and cell-cell interactions more precisely in living embryos to extract quantitative information?
1. An In Vivo Analysis of the Mechanisms of Neural Crest Migration
     Disruption of a neural crest cell’s ability to interpret environmental signals or control the temporal dynamics of its cellular processes lead to migratory patterning defects. We are investigating the role of the embryonic microenvironment in signaling and modulating neural crest migration, with particular focus on neuropilin/semaphorin (cranial) and Eph/ephrin/N-cadherin (trunk) interactions. We are integrating this work with a study to determine the control of the temporal dynamics of neural crest cell migratory behaviors, focusing on the role of the small RhoGTPases. Our data suggest that neural crest cell migration to target sites and formation of peripheral structures are separable processes modulated by distinct molecular families.

2. The Chick Embryonic Microenvironment as a Model for Cancer Studies
     The chick embryonic neural crest-rich microenvironment provides an attractive model system to explore tumor cell reprogramming and metastatic ability. We have shown that human metastatic melanoma cells transplanted into the embryonic chick neural tube migrate to host neural crest cell target sites, do not form tumors, and a subset of these tumor cells are reprogrammed to a neural crest cell-like phenotype. We hypothesize that the microenvironment and cell-cell interactions associated with the neural crest-rich regions of the chick embryo contain informational cues with the potential to revert aggressive tumor cells to a multipotent, plastic phenotype. We are currently investigating the functional role of key molecular mechanisms that modulate neural crest migration to determine the relevance of these signaling pathways involved in the control of tumor cell fate determination and reprogramming of the metastatic phenotype.

3. Development of Innovative Tools for Tracing Cell Movements in Embryos
     Relatively little is known about how migratory cells interpret and integrate signals from the microenvironment and other cells, yet our ability to distinctly follow cell movements in vivo is hindered by inaccurate, invasive labeling techniques. We are exploring photoactivation to selectively mark single and small groups of cells using targeted laser excitation and multicolor, multispectral imaging to more accurately identify and trace cell movements. We apply these techniques to study cell-neighbor relationships and cell communication in living embryos.

Academic Appointment: Assistant Professor, Department of Anatomy & Cell Biology, The University of Kansas School of Medicine

Selected publications

Kulesa PM, Teddy JM, Stark DA, Smith SE, McLennan R. Neural Crest Invasion is Spatially-Ordered Progression Into the Head with Higher Cell Proliferation at the Migratory Front as Revewaled by the Photactivatable Protein, KikGR. Dev Biol. 2008.

Rupp PA, Kulesa PM. A role for RhoA in the two-phase migratory pattern of post-otic neural crest cells. Dev Biol. 2007. Abstract

Kulesa PM, Schnell S, Rudloff S, Baker RE, Maini PK. From segment to somite: Segmentation to epithelialization analyzed within quantitative frameworks. Dev Dyn. 2007;236:1392-1402. Abstract

Stark DA, Kulesa PM. An in vivo comparison of photoactivatable fluorescent proteins in an avian embryo model. Dev Dyn. 2007. Abstract

Hendrix MJC, Seftor EA, Seftor REB, Kasemeier-Kulesa J, Kulesa PM, Postovit L-M. Reprogramming metastatic tumor cells with embryonic microenvironments. Nat Rev Cancer. 2007;7:246-255.

McLennan R, Kulesa PM. In vivo analysis reveals a critical role for neuropilin-1 in cranial neural crest cell migration in chick. Dev Biol. 2006

Kasemeier-Kulesa JC, Bradley R, Pasquale EB, Lefcort F, Kulesa PM. Eph/ephrins and N-cadherin coordinate to control the pattern of sympathetic ganglia. Development. 2006;133:4839-4847. Abstract

Kulesa PM, Kasemeier-Kulesa JC, Teddy JM, Margaryan NV, Seftor EA, Seftor RE, Hendrix MJ. Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment. Proc Natl Acad Sci U S A. 2006;103:3752-3757. Abstract

Kulesa PM, Lu CC, Fraser SE. Time-Lapse Analysis Reveals a Series of Events by Which Cranial Neural Crest Cells Reroute around Physical Barriers. Brain Behav Evol. 2005;66:255-265. Abstract

Stark D, Kulesa PM. In vivo marking of single cells in chick embryos using photoactivation of GFP. Current Protocols in Cell Biology. 2005; Supplement 28:12.18.11-12.18.11.

Teddy JM, Lansford R, Kulesa PM. Four-Color, 4D Time-Lapse Confocal Imaging of Chick Embryos. Biotechniques. 2005;39:703-710.

Stark DA, Kulesa PM. Photoactivatable green fluorescent protein as a single-cell marker in living embryos. Dev Dyn. 2005;233:983-992. Abstract

Kasemeier-Kulesa JC, Kulesa PM, Lefcort F. Imaging neural crest cell dynamics during formation of dorsal root ganglia and sympathetic ganglia. Development. 2005;132:235-245. Abstract

Teddy JM, Kulesa PM.  In vivo evidence for short- and long-range cell communication in cranial neural crest cells. Development. 2004 Dec;131(24):6141-51. Abstract

Kulesa PM. Developmental imaging: Insights into the avian embryo. Birth Defects Res C Embryo Today. 2004 Sep;72(3):260-6. Abstract

Kulesa PM, Fraser SE. In Ovo Imaging of Avian Embryogenesis. In: R Yuste, and A Konnerth, eds. Imaging in Neuroscience and Development: A Laboratory Manual. New York: Oxford: Cold Spring Harbor Laboratory Press; Lavis Marketing; 2004:700 p.

Kasemeier J, Lefcort F, Fraser SE, Kulesa PM. A novel sagittal slice explant technique for time-lapse imaging of the formation of the chick periperal nervous system. In: R Yuste, and A Konnerth, eds. Imaging in neuroscience and development : a laboratory manual. R. Yuste and A. Konnerth ed. New York: Oxford: Cold Spring Harbor Laboratory Press; Lavis Marketing; 2004:700 p.

Kulesa PM, Ellies DL, Trainor PA. Comparative analysis of neural crest cell death, migration, and function during vertebrate embryogenesis. 2004; Dev Dyn. 229:14-29. Abstract.

Patten I, Kulesa PM, Shen MM, Fraser SE, Placzek M. . Distinct modes of floor plate induction in the chick embryo. Development. 2003;130:4809-4821. Abstract.

Kulesa PM, Fraser SE.  Cell dynamics during somite boundary formation revealed by time-lapse analysis. Science. 2002;298:991-995. Movies.

Comments about this paper may be found in Developmental Cell, 3, 605-613, The Scientist, 17, 2 (10), and Caltech News, 12 Nov.

Jones EAV, Crotty D, Kulesa PM, Waters CW, Baron MH, Fraser SE, Dickinson ME.  Dynamic in-vivo imaging of post-implantation mammalian embryos using whole embryo culture. Genesis. 2002;34:228-235.

Mathis L, Kulesa PM, Fraser SE.  FGF receptor signaling is required for the maintenance of neural progenitors during Hensen's node progression. Nat Cell Biol. 2001;3:559-566. Comments about this paper may be found in Nature Reviews Neuroscience 2, 381, Nature Cell Biology, 3 June, Cell 106, 133-136, and Caltech News, 21 June.

Kulesa PM, Bronner-Fraser M, Fraser SE. In ovo time-lapse analysis after dorsal neural tube ablation shows rerouting of chick hindbrain neural crest. Development. 2000;127: 2843-2852.

Kulesa PM, Fraser SE.  In ovo time-lapse analysis of chick hindbrain neural crest cell migration shows interactions during migration to the branchial arches. Development. 2000;127:1161-1172. Movies.

Kulesa PM, Fraser SE. Neural Crest Cell Dynamics Revealed By Time-Lapse Video Microscopy Of Whole Embryo Chick Explant Cultures. Dev Biol. 1998;204:327-344. Comments about this paper may be found in Science 288, 7 April.

Kulesa PM, Fraser SE.  Confocal imaging of living cells in intact embryos. Methods Mol Biol. 1998;122:205-222. Abstract.

Kulesa PM, Fraser SE. Segmentation of the vertebrate hindbrain: a time-lapse analysis. Intl J Dev Biol. 1998;42:385-392.

Krull CE,  Kulesa PM . Embryonic Explant and Slice Preparations for Studies of Cell Migration and Axon Guidance . In: de Pablo F, Ferrus A, Stern C, eds. 36. Cellular Techniques in Developmental Biology. New York: Academic Press;1998.

Burgess PK, Kulesa PM, Murray JD,  Alvord EC Jr.  The Interaction of Growth Rates and Diffusion Coefficients in a Three-dimensional Mathematical Model of Gliomas. J Neuropath  Exp Neurol. 1997;56:704-713

Kulesa PM,  Cruywagen GC, Lubkin SR,  Maini PK, Sneyd J, Ferguson MWJ, Murray JD. On A Model Mechanism for the Spatial Patterning of Teeth Primordia in the Alligator. J Theoret Biol. 1996;180:287-296.

Murray JD, Kulesa PM. On a dynamic reaction-diffusion mechanism for the spatial patterning of teeth primordia in the alligator. J Chem Soc Faraday Trans. 1996;92:2927-2932.

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